Zymogen activation is an important biological process that is poorly understood. All proteases are activated by the specific but limited proteolysis of a second protease, but the specific molecular determinants of zymogen activation are unclear. By using the trypsin/trypsinogen system as a model, we hope to elucidate the specific molecular determinants of serine protease activation and use this information to design a metal binding site into the trypsin zymogen that will induce activation in the presence of certain transition metals. By using the resources of the Computer Graphics Laboratory at UCSF, we have modeled putative binding sites into trypsin that are expected to yield an active protease under the desired conditions. By rationally designing and producing such an engineered trypsin variant, we will have provided a means for activating a protease without the use of additional proteases.